Factors associated with first-line antiretroviral treatment failure in adult HIV-positive patients: a case-control study from Ethiopia

This study was carried out at the ART follow-up clinic of Asella Hospital, Ethiopia. The hospital gives clinical service to a total population of about 3.5 million people. There were 3238 patients with HIV/AIDS (including those from the surrounding rural areas and nearby towns) who had an ART follow-up in the hospital of which 102 (3.2%) patients were on second-line ART.

A 1:2 matched case-control study (by age, sex and treatment duration since initiated on ART) was conducted between June 2015 to July 2017 (study period). All adult HIV-positive patients (aged ≥15 years) who were on ART for at least 6 months and whose baseline CD4 lymphocyte count and WHO HIV stage details available using the ART electronic health record of Asella Hospital were our target population. This data ranges from January 2005 to May 2017, and only patients not died and had an active follow-up at the time of the study were included. Ninety-one patients who were receiving second-line ART were selected as cases. Treatment failure status for cases was confirmed by two viral load tests (viral load ≥1000 copies/mL), performed 3 months apart as per national guideline, before a change of ART regimen. Controls were 182 patients with undetectable viral load (less than 50 copies/mL) who were taking first-line ART for at least 6 months. Details of the selection process are described below (Fig. 1).

For each case, two controls were selected using a lottery method after being matched by age, sex, and duration on ART. We used the following technique for selecting controls for each case. For example, for a case who commenced ART in June 2005, we used an electronic ART database to find two controls who were also initiated on ART in June 2005 with similar gender and within ±5 years of age of the case.

Sociodemographic and clinical characteristics of participants were assessed for their possible association with the outcome variable (ART failure) (Table 1). The variables measured before ART initiation were baseline CD4 lymphocyte count and WHO HIV stage, whereas all the other variables were retrospectively measured during patient follow-up after ART was started.

Duration on ART was defined as the total time (in months) a patient was on ART since initial enrolment into ART care excluding the period of interruptions. Discontinuation of ART for a patient currently on ART was defined as having a history of complete stoppage of ART medications for any duration; whereas missed ART follow-up meant that a patient missed a drug refill date. The ART regimen for cases was their first-line ART regimen, not their current second-line regimen.

Repeated or persistent diarrhea was defined as ≥2 episodes of diarrhea or a single episode lasting more than 2 weeks, respectively. We used the term psychiatric illness in patients who were diagnosed with a disorder listed in the Diagnostic and Statistical Manual of Mental Disorders IV [24]. Tuberculosis (TB) co-infection was defined as an active TB disease requiring a curative therapy with anti-TB medications. Alcohol use was defined as the use of alcoholic beverages in any amount. A main-diet constitutes the usual sum of food consumed by participants in a stable manner for years. Poor drug absorption was assumed to be present in those patients who experienced diarrhea (repeated or persistent) and frequently eat wheat or barely. For variables measuring co-existing chronic infections, we presumed that these diseases were either acquired during a similar high-risk behavior that led to the acquisition of HIV itself (hepatitis B virus (HBV), hepatitis C virus (HCV), and syphilis) or acquired early in life (HBV and Helicobacter pylori (H. pylori) infection).

The questionnaire was first developed in English and translated into local languages, Oromiffa and Amharic, and cross-checked for consistency. It was piloted, modified and validated. Training was provided for the study team before the start of the project. The research team included the three investigators, two registered nurses who assisted patients to complete the questionnaire, five laboratory technicians and an IT professional to record all the observations into Epi-info software daily. The investigators continuously monitored the data collection process throughout the study. Data completeness was regularly checked, and any missing data were obtained on the subsequent follow-up of patients.

Data from Epi-Info was exported to SPSS statistics version 23.0. Descriptive statistics were used to present socio-demographic and clinical characteristics. Bivariate logistic regression analysis was carried out, and independent variables with p-values of ≤0.2 were included in multivariate logistic regression analysis. Prior to the multivariate analysis, multicollinearity diagnostics was performed, and there were no significant interactions between independent variables. Adjusted odds ratios (AOR) with 95% confidence intervals (CIs) were used as an effect measure. A p-value of equal or less than 0.05 was considered as significant. The matching factors (age, sex and duration of ART) were included in the adjusted analysis.

Ethical approval was obtained from the Arsi University College of Health Sciences Ethics Review Board. Informed consent was obtained from study participants. Information gathered from respondents was treated confidentially, and the norm of the community was considered and respected in the process of data collection. Patients with abnormal findings were referred to the treating physician and were provided with the appropriate care.

Of all 273 study participants, 55% were males. The median age of the participants was 40 years. The median duration of treatment was 69 months. Most of the participants were Orthodox Christian 187 (69%), married 160 (59%), and literate 234 (86%). Approximately three-quarters of patients were living in the urban area, and 267 (98%) were employed (Table 1).

When we compare the characteristics of cases with controls in terms of age, sex and duration of ART; they were roughly comparable in a 1:2 ratio. Compared with controls, cases were six times more affected with active tuberculosis and four times more likely to have persistent diarrhea (Tables 1 and 2).